A preliminary evaluation of glial cell line‐derived neurotrophic factor (GDNF) levels in cerebrospinal fluid across various gestational ages and clinical conditions of the neonate

Rajkumar, Rahul; Bhaya, Bhavana; Mamilla, Divya; Czech, Theresa; Kisseih, Esther; Saini, Arun; Chouthai, Nitin

doi:10.1016/j.ijdevneu.2017.10.001

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…In contrast, our study demonstrates that the secretion of another important neurotrophic factor, GDNF, was significantly increased in UCB under stress-related conditions during the preterm labor. Similar to our results, Rajkumar et al observed that cord blood GDNF levels were significantly higher in preterm newborns compared to term newborns [66]. GDNF is a potent neurotrophin that protects the central and peripheral nervous system against degeneration.…”

Section: Discussionsupporting

confidence: 92%

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

Gródecka-Szwajkiewicz

Ulańczyk

Zagrodnik

et al. 2020

IJMS

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Objectives: Premature birth, defined as less than 37 weeks gestation, affects approximately 12% of all live births around the world. Advances in neonatal care have resulted in the increased survival of infants born prematurely. Although prematurity is a known risk factor for different cardiovascular diseases, little is known about the pathophysiology of vasculature during premature gestation and angiopoietic factors network during premature birth. Aims: The objective of this study was to determine whether the profile of several pro-angiogenic and anti-angiogenic factors in umbilical cord blood (UCB) is different in healthy appropriate-for-gestational-age preterm newborns and normal term babies. The second aim of this study was to investigate the microRNA (miRNAs) expression profile in UCB from preterm labor and to detect miRNAs potentially taking part in control of angogenesis-related processes (Angio-MiRs). Methods: Using an immunobead Luminex assay, we simultaneously measured the concentration of Angiogenin, Angiopoietin-1, FGF-acidic, FGF-basic, PDGF-aa, PlGF, VEGF, VEGF-D, Endostatin, Thrombospondin-2, NGF, BDNF, GDNF, and NT-4 in UCB samples collected from the preterm (n = 27) and term (n = 52) delivery. In addition, the global microRNA expression in peripheral blood mononuclear cells (PBMCs) circulating in such UCB samples was examined in this study using microarray MiRNA technique. Results: The concentrations of five from eight measured pro-angiogenic factors (VEGF, Angiopoietin-1, PDGF-AA, FGF-a, and FGF-b) were significantly lower in UCB from preterm newborns. On the contrary, two angiostatic factors (Endostatin and Thrombospondin-2) were significantly up-regulated in preterm UCB. Among analyzed neurotrophins in preterm newborns, the elevated UCB concentration was found only in the case of GDNF, whereas BDNF was significantly reduced. Moreover, two angiopoietic factors, VEGF-D and PlGF, and two neurotrophins, NT4 and NGF, did not differ in concentration in preterm and term babies. We also discovered that among the significantly down-regulated miRNAs, there were several classical Angio-MiRs (inter alia MiR-125, MiR-126, MiR-145, MiR-150, or MiR155), which are involved in angiogenesis regulation in newborn after preterm delivery. Conclusions: This is the first report of simultaneous measurements of several angiopoietic factors in UCB collected from infants during preterm and term labor. Here, we observed that several pro-angiogenic factors were at lower concentration in UCB collected from preterm newborns than term babies. In contrast, the two measured angiostatic factors, Endostatin and Thrombospondin-2, were significantly higher in UCB from preterm babies. This can suggest that distinct pathophysiological contributions from differentially expressed various angiopoietic factors may determine the clinical outcomes after preterm birth. Especially, our angiogenesis-related molecules analysis indicates that preterm birth of healthy, appropriate-for-gestational-age newborns is an “anti-angiogenic state” that may provide an increased risk for improper development and function of cardiovascular system in the adulthood. This work also contributes to a better understanding of the role of miRNAs potentially involved in angiogenesis control in preterm newborns.

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Section: Discussionsupporting

confidence: 92%

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

Gródecka-Szwajkiewicz

Ulańczyk

Zagrodnik

et al. 2020

IJMS

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“…Therefore, identifying additional biomarkers for the early identification of neuronal injury, in addition to cranial ultrasonography, is crucial for improving therapeutic outcomes 27. Various CSF biomarkers, including TGFß‐1 28, VEGF 29, BDNF 20, GDNF 30, and proinflammatory cytokines, such as IL‐1α 31, IL‐1ß 32, CCL‐3, and CCL‐19 31 have been used to diagnose brain injury and predict neurodevelopmental outcomes. In a previous study of brain‐specific proteins in the CSF, glial fibrillary acidic protein level was found to be substantially higher in infants with IVH and PHH than in normal infants.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

Ahn

Chang

Sung

et al. 2018

Stem Cells Translational Medicine

126

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We previously demonstrated that transplanting mesenchymal stem cells (MSCs) improved recovery from brain injury induced by severe intraventricular hemorrhage (IVH) in newborn rats. To assess the safety and feasibility of MSCs in preterm infants with severe IVH, we performed a phase I dose‐escalation clinical trial. The first three patients received a low dose of MSCs (5 × 106 cells/kg), and the next six received a high dose (1 × 107 cells/kg). We assessed adverse outcomes, including mortality and the progress of posthemorrhagic hydrocephalus. Intraventricular transplantation of MSCs was performed in nine premature infants with mean gestational age of 26.1 ± 0.7 weeks and birth weight of 808 ± 85 g at 11.6 ± 0.9 postnatal days. Treatment with MSCs was well tolerated, and no patients showed serious adverse effects or dose‐limiting toxicities attributable to MSC transplantation. There was no mortality in IVH patients receiving MSCs. Infants who underwent shunt surgery showed a higher level of interleukin (IL)‐6 in cerebrospinal fluid (CSF) obtained before MSC transplantation in comparison with infants who did not receive a shunt. Levels of IL‐6 and tumor necrosis factor‐α in initially obtained CSF correlated significantly with baseline ventricular index. Intraventricular transplantation of allogeneic human UCB‐derived MSCs into preterm infants with severe IVH is safe and feasible, and warrants a larger, and controlled, phase II study. Stem Cells Translational Medicine 2018;7:847–856

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“…Elevated levels of inflammatory proteins in blood or cerebrospinal fluid (CSF) are associated with perinatal brain injury and increased risk of adverse neurodevelopmental outcome ( Yoon et al, 1996 ; Nelson et al, 1998 ; Savman et al, 1998 ; Bartha et al, 2004 ; Viscardi et al, 2004 ; Carlo et al, 2011 ; Armstrong-Wells et al, 2015 ; Basu et al, 2015 ). However, protein levels in plasma do not always correlate with those in the CSF in preterm infants with white matter injury, demonstrating that blood analyses may not reflect events in the CNS ( Ellison et al, 2005 ; Rajkumar et al, 2018 ). Furthermore, a comprehensive assessment of inflammation-associated factors in preterm CSF has not been carried out.…”

Section: Introductionmentioning

confidence: 99%

The Cerebrospinal Fluid Inflammatory Response to Preterm Birth

et al. 2018

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Background: Preterm birth is the leading risk factor for perinatal white matter injury, which can lead to motor and neuropsychiatric impairment across the life course. There is an unmet clinical need for therapeutics. White matter injury is associated with an altered inflammatory response in the brain, primarily led by microglia, and subsequent hypomyelination. However, microglia can release both damaging and trophic factors in response to injury, and a comprehensive assessment of these factors in the preterm central nervous system (CNS) has not been carried out.Method: A custom antibody array was used to assess relative levels of 50 inflammation- and myelination-associated proteins in the cerebrospinal fluid (CSF) of preterm infants in comparison to term controls.Results: Fifteen proteins differed between the groups: BDNF, BTC, C5a, FasL, Follistatin, IL-1β, IL-2, IL-4, IL-9, IL-17A, MIP-1α, MMP8, SPP1, TGFβ, and TNFβ (p < 0.05). To investigate the temporal regulation of these proteins after injury, we mined a gene expression dataset of microglia isolated from a mouse model of developmental white matter injury. Microglia in the experimental model showed dynamic temporal expression of genes encoding these proteins, with an initial and sustained pro-inflammatory response followed by a delayed anti-inflammatory response, and a continuous expression of genes predicted to inhibit healthy myelination.Conclusion: Preterm CSF shows a distinct neuroinflammatory profile compared to term controls, suggestive of a complex neural environment with concurrent damaging and reparative signals. We propose that limitation of pro-inflammatory responses, which occur early after perinatal insult, may prevent expression of myelination-suppressive genes and support healthy white matter development.

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A preliminary evaluation of glial cell line‐derived neurotrophic factor (GDNF) levels in cerebrospinal fluid across various gestational ages and clinical conditions of the neonate

Abstract: GDNF levels in preterm newborns were higher in cord blood and lower in CSF as compared to term newborns. It is important to further study circulating and CSF-GDNF levels in newborns at different gestational ages and clinical conditions.

Cited by 5 publications

References 28 publications

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

The Cerebrospinal Fluid Inflammatory Response to Preterm Birth

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